WO2017013591A1 - Formulation liquide stabilisée de lévothyroxine - Google Patents

Formulation liquide stabilisée de lévothyroxine Download PDF

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Publication number
WO2017013591A1
WO2017013591A1 PCT/IB2016/054308 IB2016054308W WO2017013591A1 WO 2017013591 A1 WO2017013591 A1 WO 2017013591A1 IB 2016054308 W IB2016054308 W IB 2016054308W WO 2017013591 A1 WO2017013591 A1 WO 2017013591A1
Authority
WO
WIPO (PCT)
Prior art keywords
levothyroxine
sodium
stable
agents
pharmaceutical formulation
Prior art date
Application number
PCT/IB2016/054308
Other languages
English (en)
Inventor
Kocherlakota Chandrashekhar
Banda Nagaraju
Original Assignee
Leiutis Pharmaceuticals Pvt Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Leiutis Pharmaceuticals Pvt Ltd filed Critical Leiutis Pharmaceuticals Pvt Ltd
Priority to US15/745,615 priority Critical patent/US11154498B2/en
Publication of WO2017013591A1 publication Critical patent/WO2017013591A1/fr
Priority to US17/494,450 priority patent/US20220047509A1/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
    • A61K31/198—Alpha-aminoacids, e.g. alanine, edetic acids [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner

Definitions

  • Thyroxine active drugs are known for both therapeutic and prophylactic treatment of thyroid disorders.
  • the thyroid accomplishes its regulation functions by producing the hormones L-triiodothyronine (lio thyronine; T3) and L-thyroxine (levothyroxine; T4).
  • the physiological actions of thyroid hormones are produced predominantly by T3, the majority of which (approximately 80%) is derived from T4 by deiodination in peripheral tissues.
  • T4 administration of levothyroxine sodium provides T4 to a patient. Once absorbed, the administered T4 behaves identically to T4 that otherwise would be secreted by the thyroid gland of the patient, and binds to the same serum proteins, providing a supply of circulating T4-thyroglobulin in the patient.
  • the administered T4 may be deiodinated in vivo to T3. As a result, a patient receiving appropriate doses of levothyroxine sodium will exhibit normal blood levels of T3, even when the patient's thyroid gland has been removed or is not functioning.
  • Levothyroxine sodium is prescribed for thyroid hormone replacement therapy in cases of reduced or absent thyroid function e.g., ailments such as myxedema, cretinism and obesity.
  • Levothyroxine sodium is quite unstable, hygroscopic and degrades rapidly when subjected to high humidity, light or high temperature. Because of the physicochemical properties of the drug, formulations of levothyroxine sodium have extremely short stability duration, worsened under conditions of high humidity and temperature.
  • Levothyroxine sodium is available in the form of capsules, tablets and parenteral dosage forms.
  • Levothyroxine sodium for injection is available as sterile lyophilized product for parenteral administration containing 100 mcg/vial, 200 mcg/vial and 500 mcg/vial.
  • Conventional formulations of levothyroxine sodium for injection are preservative-free lyophilized powders containing synthetic crystalline levothyroxine sodium, mannitol, tribasic sodium phosphate, and sodium hydroxide. These conventional formulations typically contain lOmg mannitol, 70( g of tribasic sodium phosphate and lOOmcg or 200mcg or 500mcg of levothyroxine sodium.
  • Administration of the conventional formulation involves reconstitution of the lyophilized powder in 5mL of 0.9% sodium chloride injection, to provide injectable solutions having levothyroxine sodium concentrations of 20mcg/mL, 40mcg/mL or lOOmcg/mL.
  • Levothyroxine has extremely short stability, worsened under conditions of high humidity and temperature. Due to this instability, Levothyroxine injectable formulations are used in the form of lyophilized formulations that are dissolved in 0.9% sodium chloride Injection immediately before injection. The present inventors have developed stable liquid formulations of Levothyroxine intended for parenteral administration.
  • One object of the invention provides stable liquid parenteral pharmaceutical formulation of Levothyroxine.
  • Another aspect of the invention provides stable liquid parenteral pharmaceutical formulation of Levothyroxine comprising Levothyroxine, buffering agents, one or more solvents and other pharmaceutically acceptable excipients thereof.
  • Yet another aspect of the invention provides liquid parenteral pharmaceutical formulation of Levothyroxine comprising Levothyroxine sodium, buffering agents, stabilizing agents, one or more solvents and other pharmaceutically acceptable excipients thereof.
  • the present invention relates to stable liquid parenteral formulation of Levothyroxine, and more particularly to stable Levothyroxine liquid formulation comprising of buffering agents, stabilizing agents, solvents and other pharmaceutically acceptable excipients thereof.
  • Levothyroxine refers to the pharmaceutically acceptable salts, solvates, hydrates and anhydrous forms thereof.
  • the formulations of the present invention preferably comprise Levothyroxine sodium.
  • liquid parenteral formulations of Levothyroxine refers to formulations that contain Levothyroxine in dissolved or solubilised form and are intended to be used as such or upon dilution in intravenous diluents.
  • Levothyroxine sodium is quite unstable, hygroscopic and degrades rapidly when subjected to high humidity, light or high temperature. Degradation is further enhanced by the presence of water. Hence, attempts to develop an intravenous preparation of Levothyroxine were limited.
  • the inventors of the present invention have surprisingly found that it is possible to develop stable liquid parenteral pharmaceutical formulation of Levothyroxine, despite its rapid degrading nature.
  • liquid parenteral pharmaceutical formulation of Levothyroxine comprising:
  • v. optionally one or more pharmaceutically acceptable excipients selected from pH adjusting agents and anti-oxidants.
  • Stabilizing agents used in the formulation include, but not limited to sodium iodide, potassium iodide and the like.
  • the pharmaceutical compositions of the present invention may also contain solubilizing agents such as cyclodextrins. These agents may be used in the formulation to maintain the solubility and stability of levothyroxine sodium during the entire shelf life of the formulation.
  • Suitable cyclodextrins include but not limited to ⁇ , ⁇ and ⁇ -cyclodextrin and cyclodextrins modified with alkyl-, hydroxy alkyl-, dialkyl-, and sulfoalkyl-ether modified cyclodextrins such as methyl or hydroxypropyl ⁇ - cyclodextrins (HPpCD), methyl-and-ethyl-P-cyclodextrin, sulfoalkylether-substituted beta-cyclodextrin, sulfobutylether-P-cyclodextrin (SBECD) and the like.
  • HPpCD methyl or hydroxypropyl ⁇ - cyclodextrins
  • SBECD sulfoalkylether-substituted beta-cyclodextrin
  • SBECD sulfobutylether-P-cyclodextrin
  • Suitable buffering agents include amino acids such as arginine, alanine, histidine, glycine and lysine; citrate, glutamate, bicarbonate, tartrate, benzoate, lactate, gluconate, TRIS, acetate, meglumine, borate and phosphate buffer.
  • Suitable solvents include, but not limited to dimethylacetamide, dimethyl sulfoxide, N- methylpyrrolidone, dimethylisosorbide, ethanol, propylene glycol, polyethylene alcohol, propylene glycol esters, polyethylene glycols, glycerine, water and the like. Preferred solvents are water and propylene glycol.
  • Suitable pH adjusting agents include sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, ammonium carbonate, hydrochloric acid, citric acid, lactic acid, phosphoric acid, sodium phosphate, sulfuric acid and the like.
  • the pharmaceutical compositions of the present invention may also contain one or more anti-oxidants such as sodium sulfite, sodium bisulfite, sodium metabisulfite, sodium thiosulphate, sodium formaldehyde sulfoxylate, citric acid, tocopherol, butylated hydroxy anisole, butylated hydroxy toluene, monothioglycerol, ascorbic acid, sodium ascorbate and propyl gallate.
  • Table 1 Evaluation of different buffering agents for their suitability in the formulation.
  • buffering agent(s) selected from aminoacids such as arginine, alanine, histidine, glycine and lysine; citrate, glutamate, bicarbonate, tartrate, benzoate, lactate, gluconate, TRIS, acetate, borate and phosphate buffer
  • one or more solvents selected from the group comprising water, polyethylene glycol, ethanol, propylene glycol and glycerine
  • v. optionally one or more pharmaceutically acceptable excipients selected from pH adjusting agents and anti-oxidants.
  • Levothyroxine formulation prepared according to the invention was tested for stability at 2-8°C, 25°C and 60°C for a period of 1 month.
  • the stability data of the invention formulation is summarized in table 2.
  • L-Arginine was added to the manufacturing vessel containing water for injection, sodium acetate anhydrous was added to the above solution and stirred well. Potassium hydroxide was added to the above solution followed by the addition of sodium metabisulfite and sodium iodide. The solution was cooled to 2-8°C. Levothyroxine sodium was added to the above solution and stirred till a homogeneous solution was obtained.
  • Arginine was added to the manufacturing vessel containing water for injection, sodium acetate anhydrous was added to the above solution and stirred well. Potassium hydroxide was added to the above solution followed by the addition of sodium iodide. The solution was cooled to 2-8°C. Levothyroxine sodium was added to the above solution and stirred till a homogeneous solution was obtained.
  • SBECD was added to the manufacturing vessel containing water for injection followed by the addition of Levothyroxine sodium. Arginine was added and stirred well, till a clear solution was obtained. Sodium iodide was added to the above solution. The pH of the solution was adjusted to 6.0 + 1.0 (if necessary) with sodium hydroxide/hydrochloric acid.

Abstract

La présente invention concerne des formulations liquides stabilisées de lévothyroxine ou d'un sel pharmaceutiquement acceptable de celle-ci, destinées à une administration parentérale. L'invention concerne également un procédé de préparation de ces compositions.
PCT/IB2016/054308 2015-07-22 2016-07-20 Formulation liquide stabilisée de lévothyroxine WO2017013591A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US15/745,615 US11154498B2 (en) 2015-07-22 2016-07-20 Stabilized liquid formulation of levothyroxine
US17/494,450 US20220047509A1 (en) 2015-07-22 2021-10-05 Stabilized liquid formulation of levothyroxine

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN3770/CHE/2015 2015-07-22
IN3770CH2015 2015-07-22

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US15/745,615 A-371-Of-International US11154498B2 (en) 2015-07-22 2016-07-20 Stabilized liquid formulation of levothyroxine
US17/494,450 Continuation US20220047509A1 (en) 2015-07-22 2021-10-05 Stabilized liquid formulation of levothyroxine

Publications (1)

Publication Number Publication Date
WO2017013591A1 true WO2017013591A1 (fr) 2017-01-26

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2016/054308 WO2017013591A1 (fr) 2015-07-22 2016-07-20 Formulation liquide stabilisée de lévothyroxine

Country Status (2)

Country Link
US (2) US11154498B2 (fr)
WO (1) WO2017013591A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9782376B1 (en) 2016-12-01 2017-10-10 Fresenius Kabi Usa Llc Levothyroxine liquid formulations
WO2019023791A1 (fr) * 2017-07-31 2019-02-07 Apollo Pharmaceuticals Inc. Formulations de lévothyroxine
GB2558498B (en) * 2015-11-04 2020-10-14 Leiutis Pharm Pvt Ltd Novel levothyroxine formulations for oral use

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020160123A1 (fr) * 2019-01-30 2020-08-06 Hikma Pharmaceuticals Usa Inc. Formulations liquides de lévothyroxine
US11400068B2 (en) * 2020-06-12 2022-08-02 Somerset Therapeutics Llc Liquid ready-to-use formulation of levothyroxine

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004060353A1 (fr) * 2002-12-19 2004-07-22 Pharmacia Corporation Dispersions solides comprenant un medicament hygroscopique et/ou deliquescent
WO2011104625A1 (fr) * 2010-02-23 2011-09-01 Supratek Pharma, Inc. Compositions de cyclopolysaccharide

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2889363A (en) 1955-12-09 1959-06-02 Baxter Laboratories Inc Process for producing thyroxine
US2889364A (en) 1957-05-03 1959-06-02 Baxter Laboratories Inc Process for producing thyroxine
US5635209A (en) * 1995-10-31 1997-06-03 Vintage Pharmaceuticals, Inc. Stabilized composition of levothyroxine sodium medication and method for its production
ES2224184T3 (es) 1995-11-14 2005-03-01 ABBOTT GMBH & CO. KG Preparaciones estabilizadas de hormonas tiroideas y metodos para su fabricacion.
HUT75956A (en) * 1995-11-29 1997-05-28 Cyclolab Pharmaceutical composition containing thyroxine
WO2003072060A2 (fr) * 2002-02-27 2003-09-04 Immunex Corporation Preparation de polypeptides
GB0222500D0 (en) * 2002-09-27 2002-11-06 Unilever Plc Packaged personal care compositions
WO2007077252A1 (fr) 2006-01-06 2007-07-12 Intervet International B.V. Composition d'hormone thyroidienne liquide concentree
US20090105314A1 (en) * 2006-05-15 2009-04-23 Takeda Pharmaceutical Company Limited Pharmaceutical Agent
EP2750664A1 (fr) 2011-08-30 2014-07-09 Fresenius Kabi USA, LLC Formulations de lévothyroxine
US20140073965A1 (en) 2012-09-11 2014-03-13 Nellcor Puritan Bennett Llc Methods and systems for qualifying physiological values based on positive and negative values

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004060353A1 (fr) * 2002-12-19 2004-07-22 Pharmacia Corporation Dispersions solides comprenant un medicament hygroscopique et/ou deliquescent
WO2011104625A1 (fr) * 2010-02-23 2011-09-01 Supratek Pharma, Inc. Compositions de cyclopolysaccharide

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2558498B (en) * 2015-11-04 2020-10-14 Leiutis Pharm Pvt Ltd Novel levothyroxine formulations for oral use
US9782376B1 (en) 2016-12-01 2017-10-10 Fresenius Kabi Usa Llc Levothyroxine liquid formulations
WO2018102145A1 (fr) * 2016-12-01 2018-06-07 Fresenius Kabi Usa, Llc Formulations liquides de lévothyroxine
US10398669B2 (en) 2016-12-01 2019-09-03 Fresenius Kabi Usa, Llc Levothyroxine liquid formulations
US11135190B2 (en) 2016-12-01 2021-10-05 Fresenius Kabi Usa, Llc Levothyroxine liquid formulations
WO2019023791A1 (fr) * 2017-07-31 2019-02-07 Apollo Pharmaceuticals Inc. Formulations de lévothyroxine

Also Published As

Publication number Publication date
US20180214374A1 (en) 2018-08-02
US11154498B2 (en) 2021-10-26
US20220047509A1 (en) 2022-02-17

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